The present invention relates to a method for making 2-(N-phenylamino)benzoic acids by coupling a benzoic acid and an aniline.
The compound 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamine is being developed as a selective MEK-1 inhibitor for the treatment of proliferative diseases, including cancer, restenosis, psoriasis, and atherosclerosis. See, for example, U.S. Patent Application No. 60/051,440, filed Jul. 1, 1997, or PCT Published patent Application Number WO 99/01426, published Jan. 14, 1999, which are hereby incorporated by reference. To make 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamine, one of the intermediates that is needed is a 2-(N-phenylamino)benzoic acid. The present invention provides a method for making 2-(N-phenylamino)benzoic acids.
The present invention provides a method for making 2-(N-phenylamino)benzoic acids, the method comprising the step of reacting a benzoic acid having the Formula I 
and an aniline having the Formula II 
with an alkaline metal hexamethyldisilazide to form a 2-(N-phenylamino)benzoic acid having the Formula III 
wherein
each R is independently hydrogen, halogen, C1-C6 alkyl, xe2x80x94OC1-C6 alkyl, CN, or NO2.
In a preferred embodiment of the invention, the alkaline metal hexamethyldisilazide is lithium hexamethyldisilazide (LiHMDS).
In another preferred embodiment of the invention, the alkaline metal hexamethyldisilazide is about 3 equivalents or more with respect to the benzoic acid.
In another preferred embodiment of the invention, the halo substituent in the 2 position of the benzoic acid is fluorine.
In another preferred embodiment of the invention, the reaction is carried out at about xe2x88x9278xc2x0 C. to about 25xc2x0 C. in a polar, aprotic solvent.
In a more preferred embodiment, the solvent is tetrahydrofuran.
In another preferred embodiment of the invention, the benzoic acid is 2,3,4,-trifluorobenzoic acid and the aniline is 2-chloro-4-iodoaniline.
In another preferred embodiment of the invention, the benzoic acid and the aniline are present in about a 1:1 molar ratio.
In another preferred embodiment of the invention, one or more of the substituents R on the aniline is an electron donating group.
In another preferred embodiment of the invention, the electron donating group on the aniline is xe2x80x94OCH3.